Process for making acylated



Q I I PROCESS FOR MAKING .ACYLATED LEUCOMETHYLENE BLUE Saul Rex Buc,Easton, Pa., assignorto General Aniline & Film Corporation, New York,N.Y-.,,a corporation of Delaware No Drawing. Application December 6,1957: 7 Serial No. 7005 968 17 Claims. (Cl. 2 60-"-243) This inventionrelates to a new process for preparing acylated leucomethylene blueinexcellent yields and of an outstanding andsuperior degree of purity, andin particular to the preparation of benzoyl and substituted ben-.

zoyl leucomethylene blues.

Benzoyl leucomethylene blue has recently'come tothe forefront as animportant product useful in the ma'nufao ture of the so-calledcarbonless carbon papers. With such papers, copies are produced in amanner similar to carbon copies except that no carbon paper interleavmgis necessary; By the" mere application'oflpressur'e a markis produceddue to the chemical interaction of. thezbenzoyl leucomethylene blue withother ingredients ipresent'in or on thepaper or'in oruon anadjacentpaper. .Forsuch usage:the benzoyl leucomethylene blue must: have'no'trace ofxcolor and rnust =be ofJeXceptiOnal pnrity,that is, completelyfree of unconverted methylene blue or leucomethylene blue, and also freeof contaminating colorforming substances such as metals, for example;iron.

It is an object of this inventionto provide a new. process fonpreparingacylated leucomethylene blue and in particular benzoyl leucomethyleneblue and sub stituted of purity. a

It is a further object of this invention toprovide" a process for thepreparation of -highrquality acylated leucomethylene blue. and inparticular benzoylflleucomethylene benzoyb'leucomethylene blue of anexceptional degree" blue"and substituted benzoyl leucomethylene bliieinexa cellent yields.

Other objects will appear hereinafter asthe description proceeds. Theobjects of this invention are: accomplished by carrying out thereduction of the unconverted methylene blue under carefullycontrolledconditionsand following this step with one of acylation of the resultantleucometh-- ylene blue in the presenceof critical reagents and underselected conditions.

The general procedure involves conducting the reduction of the methyleneblue tothe leuco form thereof in the presence of a waterimmiscibleorganic liquidwhich. is a solvent 'for the desired acylatedleucomethyleneblue.

After the dyehas been converted-to theleuco form theacylation step isthen carried out in a carefully controlled acid mediumbetween a pH ofabove 3 and below 6,. and preferably at a pH'of 4,'after.-which the.acylated-leucoamethylene blue is isolated by conventional procedures.

The reduction of the dyestuif to the leuco form-is oon- Benzene TolueneXylenes- Chlorobenzene o-Dichlorobenzene 2,909,520 Patented Oct. 20,11959 m-Dichlorobenzene Trichlorobenzene Chloroform Carbon tetrachlorideTrichloro ethylene aromatic, carbocyclic acylating agents may beemployed.

Thus, in addition to benzoyl chloride, there maybe used the followingacid chlorides:

Ortho-toluoyl bromide Meta-toluoyl bromide Para-toluoyl bromidePara-toluoyl chloride Ortho-toluoyl chloride Meta-toluoyl chloride2,4-dimethyl benzoyl chloride 2,3-Xyloyl chloride 3,5 -xyloyl chlorideZ-ethyl benzoyl chloride Halo-benzoyl halide, e.g.

o-Chlorobenzoyl chloride m-Chlorobenzoyl chloride p-Chlorobenzoylchloride 2,3-dichlorobenzoyl chloride 2,4-dichlorobenzoyl chloride2,5-dichlorobenzoyl chloride 2,6-dichlorobenzoyl chloride-3,4-dich1orobenzoyl chloride 3,5-dichlorobenzoyl chloride 2,3,5-trichlorobenzoyl chloride 2,4,5-trichlorobenzoy1 chloride2,4,6-trichlorobenzoyl chloride 3,4,5-trichlorobenzoyl chloride2,3,4,5-tetrachlorobenzoyl chloride Penta-chlorobenzoyl chlorideo-Bromobenzoyl chloride m-Bromobenzoyl ,bromide p-Bromobenzoyl chlorideo-Bromobenzoyl bromide 1 m-Bromobenzoyl bromide p-Bromobenzoyl bromide3,5-dibromobenzoyl chloride 2,5-dibromobenzoyl 4-methylbenzoyl chlorideChlorotoluoyl chloride 2,6-dibromo-4-methylbenzoyl chloride2,6-dibromobenzoyl chloride 2,4-dibromobenzoyl chloride Nitro-containinghalides, e.g.

3-nitrobe nzoyl chloride S-nitrobenzoyl bromide 4-nitrobenzoyl chloride4-nitrobenzoyl bromide 2,4-dinitrobenzoyl chloride 2,6-dinitrobenzoylchloride 3,5-dinitrobenzoyl chloride 3-nitro-2-methylbenzoyl chloride5-nitro-2-methylbenzoyl chloride 2-nitro-3-methylbenzoyl chloride2-nitro-4-methylbenzoyl chloride 3-hitro-4-methylbenzoyl chloride3,5-dinitro-4-methylbenzoyl chloridev 3,5 -.dinitrobenzoyl bromideHalo-'nitro-containing halides, e.g.

2-bromo-4-nitrobenzoyl chloride 2-chloro-3-nitrobenzoyl chloride2-chloro-4-nitrobenzoyl chloride 2-chloro-5-nitrobenzoyl chloride3-nitro-4-bromobenzoyl chloride 3-nitro-6-bromobenzoyl chloride2,4,6-trichloro 3 -nitrobenzoyl chloride 6-bromo-3-nitro-4-methylbenzoylchloride 3,5-dinitro-4-methyl-2-bromobenzoyl chloride2-chloro-3,S-dinitrobenzoyl chloride 2-trichloromethyl benzoyl chloride2-methoxy benzoyl chloride 3-methoxy benzoyl chloride 4-methoxy benzoylchloride 2-propyloxy benzoyl chloride 3-ethoxy benzoyl chloride2-acetoxy benzoyl chloride 4-ethoxy benzoyl chloride 4-propyloxy benzoylchloride 4-isoamyloxy benzoyl chloride 4-benzyloxy benzoyl chloride4-acetoxy benzoyl chloride Carbomethoxy salicylic acid chloride2-acetoxy-3-methy1 benzoyl chloride 6-acetoxy-3-methyl benzoyl chloride3,4'dimethoxy benzoyl chloride 3,5 -dimethoxy benzoyl chloridealpha-napthoyl chloride beta-naphthoyl chloride 3-chlorol -naphthoylchloride 4-methyl- -napthoyl chloride Z-methyl- -naphthoyl chloride2-bromomefhyl-a-naphthoyl bromide a-Chloro-fl-naphthoyl chlorideS-bromo-l-naphthoyl chloride l-methoxy-Z-naphthoyl chloride 1-[carbomethoxy-oxy] -2-naphthoyl chloride 3- [carbomethoxy-oxy]-2-naphthoyl chloride Orthophenyl benzoyl chloride Metaphenyl benzoylchloride Paraphenyl benzoyl chloride Methylbenzyl benzoyl chloride Ithas been discovered that the use of a metal sequestering agent in theprocess is desirable to reduce to an absolute minimum the deleteriouseffects of traces of metals in the final product. Since such traces ofmetals, and in particular iron, normally occur in most commercialchemical and reagents unless specifically excluded, and since thesemetals lead to objectionable color bodies in the final product, theirremoval is most desirable. While it is possible to employ reagentsabsolutely free of these contaminating metals, from a practicalviewpoint it is unnecessary to make this either a necessary or rigidrequirement since by the use .of sequestering agents, the

eflects of any metals present can be obviated. As suitable sequestrantsthere may be employed the following:

Ethylenediamine tetra acetic acid fl-Hydroxyethyl ethylene diarninetriacetic acid Triethanolamine Citric acid Bis-N(p-hydroxyethyl) glycineGluconic acid tartaric acid The amounts of such agents to be employed isnot critical and depends entirely on the amount of contaminating metal,since usually, only small amounts or traces of these metals are presentfrom about 1% to about 20% based on the weight of the originalunconverted dyestuff is normally sufficient. It is of course-understoodthat smaller or greater amounts may be used dictated solely by theamount of metal contaminant present. v

4 The general procedure for isolating the acylated leucomethylene blueinvolves a separation of the aqueous and nonaqueous liquid phases andrecovery of the acylated product from the non-aqueous phase usually by avacuum 5 distillation. It is advantageous before separating the twoliquid phases to adjust the pH from 4 to the alkaline side (about and totreat them with an adsorptive agent to further remove undesirableby-product and color bodies. Suitable adsorption agents include:

. 10 Decolorizing charcoal Decolorizing carbon Attapulgus clay andmixture of these agents, and the like.

In the following examples, serving to illustrate the present inventionand not being deemed limitative thereof, the amounts of the variousingredients employed are,

where not otherwise indicated, in parts by weight.

Example 1 In a stirred flask charge the following 300 ml. distilledwater 32 g. methylene blue chloride (Cl. 922) 250 ml. chlorobenzene 5 g.ethylene diamine tetra acetic acid then add 13.3 ml. of 15 N sodiumhydroxide followed by 36 g. sodium hydrosulfite. pH drops to about 6.3.After about 5 minutes add ml. benzoyl chloride. As the benzoylationproceeds, the pH drops. Let the pH drop to 4.0 and maintain it at thisvalue by adding sodium hydroxide solution as needed.

' I Continue stirring for about 2 hours at this pH. Add:

35 5 g. decolorizing charcoal and 7 g. Attapulgus clay The followingingredients are charged into a wellstirred flask:

200 ml. distilled water 1 19.3 g. methylene blue.ZnCl 75 ml. chloroformTo this mixture is then added 70 g. sodium carbonate and then, further,18 g. sodium hydrosulfite are added. After about 6 minutes add 29 ml.benzoyl chloride. The pH of the reaction mass drops as the benzoylati'onproceeds and when it reaches about a pH of 4 add a 10 N sodiumhydroxidesolution to maintain the pH at this value. Continue the stirring forabout 2 /2 hours at this pH and then addS g. of Attapulgus clay. Adjustthe pH to 10 by adding 10 N sodium hydroxide solution,

then filter, separate the liquid layers and discard the aqueous layer.18.2 g. of a crystalline residue of benzoyl leucomethylene, blue isrecovered by a vacuum distillation of the organic layer to dryness.Yield is 94% of theory.

Example 3 Example 4 The procedure of Example 2 is repeated employing 1100 ml. of toluene in lieu of chloroform as the waterimmiscible solvent.The yield is 19 g. of benzoyl leucomethylene blue.

As reduction proceeds, the

The yield of benzoyl- Example 5 The procedure of Example 1 is repeatedemploying 38 ml. of p-toluoyl chloride in lieu of benzoyl chloride asthe acylating agent. The yield is 37.5 of acylated product.

Example 6 The procedure of Example 3 is repeated employing in lieu ofbenzoyl chloride, 50 ml. a-naphthoyl chloride as the acylating agent.The yield is 38 g. of a-naphthoyl leucomethylene blue.

Example 7 The procedure of Example 4 is repeated using 50 ml. ofB-naphthoyl chloride in lieu of the benzoyl chloride as the acylatingagent. The yield is 38.2 g. of fi-naphthoyl leucomethylene blue.

Example 8 To the following mixture:

300 ml. H O

26 g. methylene blue.ZnCl

125 ml. trichloroethylene, and

4 g. hydroxyethyl ethylenediamine triacetic acid,

contained in a well-stirred flask add ml. of 10 N sodium hydroxidefollowed by g. of sodium hydrosulfite. After several minutes add 40 ml.of benzoyl chloride. The pH drops slowly as benzoylation proceeds. Letthe pH drop to 4 and maintain it at this value for 2 hours 'by addinga.solution of 10 N sodium hydroxide as needed. Isolate the benzoylleucomethylene blue as described in Example 1. The yield is 25 g. ofbenzoyl leucomethylene blue.

Example 9 The procedure of Example 8 is repeated employing 150 ml. ofo-dichlorobenzene in lieu of trichloroethylene. The yield is 25.2 g. ofbenzoyl leucomethylene blue.

Example 10 The procedure of Example 8 is repeated using 3 g. of thecompound citric acid as the sequestering agent. The yield is 24.8 g. ofbenzoyl leucomethylene blue.

Example 11 The procedure of Example 8 is repeated except that in theisolation of the benzoylated product 10 g. of decolorizing carbon isemployed in lieu of the charcoal-clay mixture used in that procedure.The yield of high quality benzoyl leucomethylene blue is 24.8 g.

Example 12 The procedure of Example 11 is repeated employing in lieu ofbenzoyl chloride an equivalent amount of ptoluoyl chloride. A highquality p-toluoyl leucomethylene blue is obtained.

Example 13 To a mixture of 300 m1. H 0 26 g. methylene blue.ZnCl 150 ml.benzene The procedure of Example 13 is repeated employing 175 m1.chlorobenzene as the water-immiscible solvent 6 and in lieu of benzoylchloride as the acylating agent, an equivalent amount of p-toluoylchloride is used.

Example 15 The procedure of Example 13 is repeated using ml. oftrichloroethylene as the water-immiscible solvent.

In the following examples, the procedure of Example 1 is repeated exceptthat instead of benzoyl chloride, an "equivalent amount of the recitedacylating agent is employed.

Example Acylating Agent Yield Remarks ortho-toluoyl bromide Very good-..pure product. p-chlorobenzoyl chloride...-. Excellent-.- D0.3,5-diehlorobenzoyl chloride.. .do D0. 2,3,4,5-tetrachlorobenzoyl.--..do Do.

0 loride. o-bromobenzoyl bromide .-do Do. 2,5-dibromo-4-methyl benzoyl----.do Do.

chloride. p-nitrobenzoyl bromide ..do 7 Do. 2-nigro-4-methylbenzoylchlo- -.--.do Do.

n e. abrgmo-l-nitrobenzoyl chlo- .....do Do.

n e. 2,4,6 trichloro 3 nitroben- .--..do Do.

zoyl chloride. 3,5 dinitro 4 methyl 2 do Do.

bromo benzoyl chloride. 2-trichloromethyl benzoyl .....do Do.

chloride. Z-methoxy benzoyl chloride.- ---..do Do. 3-ethoxy benzoylchloride .-do Do. 4-isoamyloxy benzoyl chloride. --..do Do. 4-acetoxybenzoyl chloride ..do Do. i benzyloxy benzoyl chl0ride-. .--..do Do.carbomethoxy salicylic acid .--.-do D0.

chloride. 3-chloro-fl-naphthoyl chloride. .----do D0. metgylbenzylbenzoyl chlo- .-.-.do Do.

In the following examples the procedure of Example 2 is repeated using,however, the following acylating agents in equivalent amounts.

In the following examples the procedure of Example 8 is repeated usingequivalent amounts of the following acylating agents in lieu of benzoylchloride.

Example Acylating Agent Yield Remarks Excellent.

1 [carbomethoxy oxy] 2 naphthoyl chloride. 3-n1ethoxybenzoylehloride--.. 4-methyl-a-naphthoyl chloride 2,4,6-trichlorobenzoylchloride. 3,5-xyloyl chloride In the following examples the procedure ofExample 13 is repeated using, additionally, citric acid as thesequestrant with the following acylating agents.

While in the specific examples and illustrations given above in mostinstances the acylating agent employed is the chloride and in someinstances the bromide, it is of course understood that any halide may beemployed the nature of which is immaterial for the purposes of thepresent invention. Other variations in and modifications of thedescribed processes which will be obvious to those skilled in the artcan be made in this invention without departing from the scope or thespirit thereof.

This application is a continuation-in-part of my application Serial No.545,794, filed November 8, 1955, now abandoned.

I claim:

1. A process for the preparation of acylated leucomethylene blue whichcomprises introducing an acyl grouping in the nitrogen atom of theleucomethylene blue by reacting said leucomethylene blue with acarbocyclic aromatic carboxylic acylating agent in an aqueous medium andin the presence of a water-immiscible solvent at a pH below about 6.

2. A process as defined in claim 1 wherein the pH is between about 3 andabout 5, inclusive.

3. A process as defined in claim 1 wherein the pH is about 4. a

4. A process as defined in claim 3 wherein the acylating agent isbenzoyl chloride.

5. A process for preparing benzoyl leucomethylene blue which comprisestreating leucomethylene blue in an aqueous medium and in the presence ofa water-immiscible organic solvent with a benzoylating agent andmaintaining a pH below about 6 during the benzoylation and isolating theresultant benzoylated product in the waterimmiscible solvent.

6. A process as defined in claim 5 wherein the pH is maintained at about4.

7. A process as defined in claim 6 wherein the organic solvent ischlorobenzene.

8. A process as defined in claim 6 wherein the organic solvent isdichlorobenzene.

9. A process as defined in claim 6 wherein the organic solvent ischloroform.

10. A process as defined in claim 5 wherein a metal sequestrant isemployed in the reaction medium.

11. A process for preparing benzoyl leucomethylene blue which comprisestreating leucomethylene blue in an aqueous medium, and in the presenceof a water-immiscible organic liquid which is a solvent for said benzoylleucomethylene blue and a metal sequestrant, with a benzoylating agent,and maintaining a pH below about 6 during the benzoylation, andisolating the resultant benzoyl leucomethylene blue.

12. A process as defined in claim 11 wherein the pH is maintained atabout 4.

13. A process as defined in claim 12 wherein the organic solvent for thebenzoyl leucomethylene blue is chlorobenzene.

14. A process as defined in claim 12 wherein the organic solvent for thebenzoyl leucomethylene blue is dichlorobenzene.

15. A process as defined in claim 12 wherein the organic solvent for thebenzoyl leucomethylene blue is chloroform.

16. A process as defined in claim 2 wherein the acylating agent ishalogenated benzoyl chloride.

17. A process as defined in claim 2 wherein the acylating agent isnitrobenzoyl chloride.

References Cited in the file of this patent UNITED STATES PATENTS2,783,227 Adams Feb. 26, 1957 2,784,186 Adams Mar. 5, 1957 FOREIGNPATENTS 113,721 Germany Sept. 28, 1900 725,275 Great Britain Mar. 2,1955 OTHER REFERENCES Cauquil et al.: Bull. Soc. Chim., vol. 17 (No.12), p. 1037, (Nov.-Dec. 1950).

1. A PROCESS FOR THE PREPARATION OF ACYLATED LWUCOMETHYLENE BLUE WHICHCOMPRISES INTRODUCING AN ACYL GROUPING IN THE NITROGEN ATOM OF THELEUCOMETHYLENE BLUE BY REACTING SAID LEUCOMETHYLENE BLUE WITH ACARBOCYCLIC AROMATIC CARBOXYLIC ACYLATING AGENT IN AN AQUEOUS MEDIUM ANDIN THE PRESENCE OF A WATER-IMMIXSCIBLE SOLVENT AT A PH BELOW ABOUT 6.